Pyridyl substituted imidazoles

ABSTRACT

The novel compounds of Formula (I) have been found to be useful cytokine suppressive agents and therefore useful in the treatment and prophylaxis of disease states mediated thereby.

This application is a 371 of PCT/US93/00675 filed Jan. 13, 1993 now WO9,314,082.

FIELD OF THE INVENTION

This invention relates to novel compounds and methods of treatinginterleukin-1 (IL-1), interleukin-8 (IL-8), and Tumor Necrosis Factor(TNF) mediated diseases.

BACKGROUND OF THE INVENTION

Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biologicalsubstances produced by a variety of cells, such as monocytes ormacrophages. IL-1 has been demonstrated to mediate a variety ofbiological activities thought to be important in immunoregulation andother physiological conditions such as inflammation See, e.g., Dinarelloet al., Rev. Infect. Disease, 6, 51 (1984)!. The myriad of knownbiological activities of IL-1 include the activation of T helper cells,induction of fever, stimulation of prostaglandin or collagenaseproduction, neutrophil chemotaxis, induction of acute phase proteins andthe suppression of plasma iron levels.

There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease.These include rheumatoid arthritis, osteoarthritis, endotoxemia and/ortoxic shock syndrome, other acute or chronic inflammatory disease statessuch as the inflammatory reaction induced by endotoxin or inflammatorybowel disease; tuberculosis, atherosclerosis, muscle degeneration,cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis,gout, traumatic arthritis, rubella arthritis, and acute synovitis.Recent evidence also links IL-1 activity to diabetes and pancreatic βcells.

Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985), reviews thebiological activities which have been attributed to IL-1. It should benoted that some of these effects have been described by others asindirect effects of IL-1.

Excessive or unregulated TNF production has been implicated in mediatingor exacerbating a number of diseases including rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions; sepsis, septic shook, endotoxic shook, gramnegative sepsis, toxic shook syndrome, adult respiratory distresssyndrome, cerebral malaria, chronic pulmonary inflammatory disease,silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusioninjury, graft vs. host reaction, allograft rejections, fever andmyalgias due to infection, such as influenza, cachexia secondary toinfection or malignancy, cachexia, secondary to acquired immunedeficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloidformation, scar tissue formation, Crohn's disease, ulcerative colitis,or pyresis.

AIDS results from the infection of T lymphocytes with HumanImmunodeficiency Virus (HIV). At least three types or strains of HIVhave been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence ofHIV infection, T-cell mediated immunity is impaired and infectedindividuals manifest severe opportunistic infections and/or unusualneoplasms. HIV entry into the T lymphocyte requires T lymphocyteactivation. Other viruses, such as HIV-1, HIV-2 infect T lymphocytesafter T Cell activation and such virus protein expression and/orreplication is mediated or maintained by such T cell activation. Once anactivated T lymphocyte is infected with HIV, the T lymphocyte mustcontinue to be maintained in an activated state to permit HIV geneexpression and/or HIV replication. Monokines, specifically TNF, areimplicated in activated T-cell mediated HIV protein expression and/orvirus replication by playing a role in maintaining T lymphocyteactivation. Therefore, interference with monokine activity such as byinhibition of monokine production, notably TNF, in an HIV-infectedindividual aids in limiting the maintenance of T cell activation,thereby reducing the progression of HIV infectivity to previouslyuninfected cells which results in a slowing or elimination of theprogression of immune dysfunction caused by HIV infection. Monocytes,macrophages, and related cells, such as kupffer and glial cells, havealso been implicated in maintenance of the HIV infection. These cells,like T-cells, are targets for viral replication and the level of viralreplication is dependent upon the activation state of the cells. SeeRosenberg et al., The Immunopathogenesis of HIV Infection, Advances inImmunology, Vol. 57, (1989)!. Monokines, such as TNF, have been shown toactivate HIV replication in monocytes and/or macrophages See Poli, etal., Proc. Natl. Acad. Sci., 87:782-784 (1990)!, therefore, inhibitionof monokine production or activity aids in limiting HIV progression asstated above for T-cells.

TNF has also been implicated in various roles with other viralinfections, such as the cytomegalia virus (CMV), influenza virus, andthe herpes virus for similar reasons as those noted.

Interleukin-8 (IL-8) is a chemotactic factor first identified andcharacterized in 1987. Il-8 is produced by several cell types includingmononuclear cells, fibroblasts, endothelial cells, and ketainocytes. Itsproduction from endothelidl cells is induced by IL-1, TNF, orlipopolysachharide (LPS). Human IL-8 has been shown to act on Mouse,Guinea Pig, Rat, and Rabbit Neutrophils. Many different names have beenapplied to IL-8, such as neutophil attractant/activation protein-1(NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF),neutophil activating factor (NAF), and T-cell lymphocyte chemotacticfactor.

IL-8 stimulates a number of functions in vitro. It has been shown tohave chemoattractant properties for neutophils, T-lymphocytes, andbasophils. In addition it induces histamine release from basophils fromboth normal and atopic individualss as well as lysozomal enzyme releaseand respiratory burst from neutrophils. IL-8 has also been shown toincrese the surface expression of Mac-1 (CD11b/CD18) on nuetophilswithout de novo protein synthesis, this may contribute to increasedadhesion of the neutrophils to vascular endothelial cells. Many diseasesare characterized by massive neutrophil infiltration. Conditionsassociated with an increased in IL-8 production (which is responsiblefor chemotaxis of neutophils into the inflammatory site) would benefitby compounds which are suppresive of IL-8 production.

IL-1 and TNF affect a wide variety of cells and tissues and thesecytokines as well as other leukocyte derived cytokines are important andcritical inflammatory mediators of a wide variety of disease states andconditions. The inhibition of these cytokines is of benefit incontrolling, reducing and alleviating many of these disease states.

There remains a need for treatment, in this field, for compounds whichare cytokine suppresive anti-inflammatory drugs (hereinafter CSAID's),i.e. compounds which are capable of inhibiting cytokines, such as IL-1,IL-6, IL-8 and TNF.

SUMMARY OF THE INVENTION

This invention relates to the novel compounds of Formula (I) andpharmaceutical compositions comprising a compound of Formula (I) and apharmaceutically acceptable diluent or carrier.

This invention also relates to a method of treating a cytokine mediateddisease, in a mammal in need thereof which comprises administering tosaid mammal an effective amount of a compound of Formula (I).

This invention more specifically relates to a method of inhibiting theproduction of IL-1 in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I).

This invention more specifically relates to a method of inhibiting theproduction of IL-8 in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I).

This invention more specifically relates to a method of inhibiting theproduction of TNF in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I).

This invention more specifically relates to a method of treating ahuman, afflicted with a human immunodeficiency virus (HIV), whichcomprises administering to said human an effective TNF inhibiting amountof a compound of Formula (I).

The novel compounds of this invention are represented by the structure:##STR1## wherein R₁ is a mono- or di- substituted 4-quinolyl, 4-pyridyl,1-imidazolyl, 1-benzimidazolyl, 4-pyrimidinyl wherein the substituent isindependently selected from the group consisting of hydrogen, C₁₋₄alkyl, halo, O--C₁₋₄ alkyl, S--C₁₋₄ alkyl, or N(R_(a))₂ ;

R_(a) is hydrogen, C₁₋₆ alkyl; or R_(a) together with the nitrogen, mayform a heterocyclic ring of 5 to 7 members, said ring optionallycontaining an additional heteroatom selected from the group consistingof oxygen, sulfur or nitrogen;

R₂ is mono- or di-substituted phenyl wherein the subsitutents areindependently selected from the group consisting of hydrogen, halo,S(O)_(m) R₅, OR₆, halo substituted C₁₋₄ alkyl, C₁₋₄ alkyl, or N(R₁₂)₂ ;

R₄ is hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₅₋₇ cycloalkenyl, heterocyclic, heterocyclicalkyl, aryl,aryl alkyl, heteroaryl, heteroaryl alkyl;

R₃ is (X)_(r) --(Q)_(s) --(Y)_(t) ;

X is hydrogen, --(C(R₁₀)₂)_(n), --NR₁₃, --O--, or S(O)_(m) ;

r is a number having a value of 0 or 1;

m is a number having a value of 0, 1 or 2;

Q is alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic,heterocyclicalkyl, aryl, arylalkyl, heteroaryl, or hetaroarylalkyl;

s is a number having a value of 0 or 1;

Y is a substituent selected from the group consisting of hydrogen, C₁₋₁₀alkyl, halo-substituted C₁₋₁₀ alkyl, halogen, --(C(R₁₀)₂)_(n) OR₈,--(C(R₁₀)₂)_(n) NO₂, --(C(R₁₀)₂)_(n) S(O)_(m') R₁₁, --(C(R₁₀)₂)_(n) SR₈,--(C(R₁₀)₂)_(n) S(O)_(m') OR₈, --(C(R₁₀)₂)_(n) S(O)_(m') NR₈ R₉, --X_(a)--P(Z)--(X_(a) R₁₃)₂, --(C(R₁₀)₂)_(n) NR₈ R₉, --(C(R₁₀)₂)_(n) CO₂ R₈,--(C(R₁₀)₂)_(n) OC(O)--R₈, --(C(R₁₀)₂)_(n) CN, --(C(R₁₀)₂)_(n) CONR₈ R₉,--(C(R₁₀)₂)_(n) C(S)NR₈ R₉, --(C(R₁₀)₂)_(n) NR₁₀ C(O)R₈, --(C(R₁₀)₂)_(n)NR₁₀ C(S)R₈, --(C(R₁₀)₂)_(n) NR₁₀ C(Z)NR₈ R₉, --(C(R₁₀)₂)_(n) NR₁₀S(O)_(m) R₁₁, --(C(R₁₀)₂)_(n) NR₁₀ C(═NCN)--S--R₁₁, --(C(R₁₀)₂)_(n) NR₁₀C(═NCN)--NR₈ R₉, --(C(R₁₀)₂)_(n) NR₁₀ C(O)C(O)--NR₈ R₉, --(C(R₁₀)₂)_(n)NR₁₀ C(O)C(O)--OR₁₀, --(C(R₁₀)₂)_(n) C(═NR₁₀)--NR₈ R₉, --(C(R₁₀)₂)_(n)--C(═NR₁₀)--ZR₁₁, --(C(R₁₀)₂)_(n) --OC(Z)--NR₈ R₉, --(C(R₁₀)₂)_(n) NR₁₀S(O)_(m) CF₃, or --(C(R₁₀)₂)_(n) NR₁₀ C(O)OR₁₀ ;

t is an integer having a value of 0, 1, 2, or 3;

Xa is independently --(C(R₁₀)₂)_(n), --NR₈ --, --O-- or --S--;

Z is oxygen or sulfur,

m' is an ingeter having a value of 1 or 2;

n is an integer having a value of 0 to 10;

R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl,C₅₋₇ cycloalkenyl, aryl, or N(R₇)2 ; provided that when m is 1 or 2 thenR₅ is not hydrogen.

R₆ is hydrogen, C₁₋₄ alkyl, halo substituted C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, or aryl;

R₇ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, aryl, or mayform a heterocyclic ring of 5 to 7 members together with the nitrogen,said ring optionally containing an additional heteroatom selected fromthe group consisting of oxygen, sulfur or nitrogen; provided that whenR₅ is N(R₇)2 then m is 1 or 2;

R₈ is hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₅₋₇ cycloalkenyl, heterocyclic, heterocyclic alkyl, aryl,aryl alkyl, heteroaryl, heteroaryl alkyl;

R₉ is hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇cycloalkyl, C₅₋₇ cycloalkenyl, aryl, aryl alkyl, heteroaryl, heteroarylalkyl or R₈ and R₉ may together form a heterocyclic ring of 5 to 7members together with the nitrogen, said ring optionally containing anadditional heteroatom selected from the group consisting of oxygen,sulfur or nitrogen;

R₁₀ is hydrogen, or C₁₋₄ alkyl;

R₁₁ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇cycloalkenyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl;

R₁₂ is hydrogen, C₁₋₄ alkyl, aryl; or may form a heterocyclic ring of 5to 7 members together with the nitrogen;

R₁₃ is hydrogen, C₁₋₁₀ alkyl, cycloalkyl, heterocylic, aryl, aryl alkyl,heteroaryl, or heteroaryl alkyl;

or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to a method of inhibiting the production ofcytokines in a mammal in need thereof which comprises administering tosaid mammal an effective mount of a compound of Formula (I).

The compounds of Formula (I) are useful in the treatment of vitalinfections, where such viruses are sensitive to upregulation by TNF orwill elicit TNF production in vivo. The viruses contemplated fortreatment herein are those that produce TNF as a result of infection, orthose which are sensitive to inhibition, such as by decreasedreplication, directly or indirectly, by the TNF inhibitors of Formula(1). Such viruses include, but are not limited to; HIV-1, HIV-2 andHIV-3, Cytomegalovirus (CMV), Influenza, adenovirus and the Herpes groupof viruses, such as but not limited to Herpes Zoster and Herpes Simplex.

This invention more specifically relates to a method of treating ahuman, afflicted with a human immunodeficiency virus (HIV), whichcomprises administering to such mammal an effective TNF inhibitingamount of a compound of Formula (I).

The compounds of Formula (I) may also be used in association with theveterinary treatment of animals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are not limited to, the lentivirusinfections such as equine infectious anaemia virus, caprine arthritisvirus, visna virus, or the maedi virus, or the retroviruses, such asfeline immunodeficiency virus (FIV), bovine immunodeficiency virus, orcanine immunodeficiency virus.

For purposes herein of nomenclature the compounds of Formula (I) arenamed by their position corresponding to: ##STR2##

Preferred compounds of Formula (I) are those wherein R₄ is hydrogen orC₁₋₁₀ alkyl. More preferred is where R₄ is hydrogen or methyl.

Preferred R₁ moieties are 4-pyridyl and 4-quinolyl. More preferred is4-pyridyl. A preferred subsitutent for all R₁ moieites is C₁₋₄ alkyl,more preferably methyl. Most preferred for R₁ is a 2-alkyl-4-pyridyl,such as 2-methyl-4-pyridyl.

Preferred R₂ substituent groups on the phenyl ring are hydrogen orhalogen. Preferred halogens are fluoro and chloro. Preferred ringsubstitution is in the 3- and 4-positions.

Preferred R₃ moieties are hydrogen, alkyl, aryl, and heteroaryl eitherattached directly to the imdiazole ring, such as methyl, phenyl,pyridine, or pyrimidine, or by attachment thru a heteroatom, such asoxygen or sulfur, including but not limited to alkoxy, thioalkyl,benzyloxy, phenoxy, all optionally substituted by Y terms. Additionallypreferred moieites for R₃ are alkyl or phenyl substituted independentlyone or more time by halogen, --(C(R₁₀)₂)_(n) OR₈, --(C(R₁₀)₂)_(n)S(O)_(m') R₁₁, --(C(R₁₀)₂)_(n) SR₈, --(C(R₁₀)₂)_(n) S(O)_(m') OR₈,--(C(R₁₀)₂)_(n) S(O)_(m') NR₈ R₉, --X_(a) --P(Z)--(X_(a) R₁₃)₂,--(C(R₁₀)₂)_(n) NR₈ R₉, --(C(R₁₀)₂)_(n) CO₂ R₈, --(C(R₁₀)₂)_(n)OC(O)--R₈, --(C(R₁₀)₂)_(n) CONR₈ R₉, --(C(R₁₀)₂)_(n) NR₁₀ C(═NCN)--NR₈R₉, or --(C(R₁₀)₂)_(n) NR₁₀ S(O)_(m) R₁₁.

More preferably the R₃ substitution is --(C(R₁₀)₂)_(n) OR₈,--(C(R₁₀)₂)_(n) S(O)_(m') R₁₁, --(C(R₁₀)₂)_(n) NR₈ R₉, --(C(R₁₀)₂)_(n)CO₂ R₈, --(C(R₁₀)₂)_(n) S(O)_(m') NR₈ R₉, or --(C(R₁₀)₂)_(n) NR₁₀S(O)_(m) R₁₁. Most preferably the subsitutents are hydroxyl, methylthio,carboxylic acid, methylamino, N,N-dimethylaminomethyl, and thesulfonamide derivatives.

When R₃ is --X_(a) --P(Z)--(X_(a) R₁₃)2, the X_(a) moiety in --X_(a)--P(Z)--(X_(a) R₁₃)2 is preferably oxygen, or the moeity --(C(R₁₀)₂)_(n)wherein n is 0 to 2, Z and the remaining Xa terms am oxygen.

A preferred subgenus of compounds for formula (I) is where 4-pyridyl,2-alkyl-4-pyridyl, or 4-quinolyl; R₄ is hydrogen or methyl, R₁₀ ishydrogen or methyl, R₈ is hydrogen or alkyl, or where appropriate R₈ andR₉ cyclize to form a 5 membered saturated heterocyclic ring, R₂ isphenyl, or phenyl mono- or di-substituted with fluoro or chloro; R₃ isalkyl, phenyl or phenyl alkyl substituted with --(C(R₁₀)₂)_(n) OR₈,--(C(R₁₀)₂)_(n) S(O)_(m') R₁₁, --(C(R₁₀)₂)_(n) SR₈, --(C(R₁₀)₂)_(n)S(O)_(m') OR₈, --(C(R₁₀)₂)_(n) S(O)_(m') NR₈ R₉, --X_(a) --P(Z)--(X_(a)R R₁₃)2, --(C(R₁₀)₂)_(n) NR₈ R₉, --(C(R₁₀)₂)_(n) CO₂ R₈, --(C(R₁₀)₂)_(n)OC(O)--R₈, --(C(R₁₀)₂)_(n) CONR₈ R₉, --(C(R₁₀)₂)_(n) NR₁₀ C(═NCN)--NR₈R₉, or --(C(R₁₀)₂)_(n) NR₁₀ S(O)_(m) R₁₁.

In all instances herein where them is an alkenyl or alkynyl moiety as asubstituent group, such as in R₅, R₇, R₈, R₉, or R₁₁ the unsaturatedlinkage, i.e., the vinylene or acetylene linkage is preferably notdirectly attached to the nitrogen, oxygen or sulfur moieties, forinstance in Y as --(C(R₁₀)₂)_(n) NR₁₀ C(Z)NR₈ R₉, C(═NR₁₀)--ZR₁₁, orOR₈.

By the term "halo" as used herein is meant all halogens, i.e., chloro,fluoro, bromo and iodo.

By the term "C₁₋₁₀ alkyl" or "alkyl" groups as used herein is meant toinclude both straight or branched chain radicals of 1 to 10 carbonatoms, unless the chain length is limited thereto, including, but notlimited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, and the like.

By the term "heterocyclic" as used herein, in any combination, such as"heterocyclic alkyl" is meant a 5-10 membered ring system in which oneor more rings contain one or more heteroatoms selected from the groupconsisting of N, O, or S; such as but not limited to pyrrolidine,piperidine, piperazine, morpholine, imidazolidine, or pyrazolidine.

By the term "aryl" as used herein is meant phenyl, or naphthyl.

By the term "heteroaryl" as used herein, in any combination, such as"heteroaryloxy", is meant a 5-10 membered aromatic ring system in whichone or more rings contain one or more heteroatoms selected from thegroup consisting of N, O or S; such as, but not limited, to quinoline,isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole,uiazole, imidazole.

By the term "sulfinyl" as used herein is meant the oxide of thecorresponding sulfide. By the term "thio" as used herein is meant thesulfide.

By the term "mammal" as used herein includes humans.

By the term "inhibiting the production of the cytokine (IL-1, IL-8 orTNF)" is meant

a) a decrease of excessive in vivo levels of the cytokine (IL-1, IL-8 orTNF) in a human to normal levels or below normal levels by inhibition ofthe in vivo release of the cytokine (IL-1, IL-8 or TNF) by all cells,including but not limited to monocytes or macrophages;

b) a down regulation, at the genomic level, of excessive in vivo levelsof the cytokine (IL-1, IL-8 or TNF) in a human to normal levels or belownormal levels; or

c) a down regulation, by inhibition of the direct synthesis of thecytokine (IL-1, IL-8 or TNF) as a postranslational event.

d) a down regulation, at the translational level, of excessive in vivolevels of the cytokine (IL-1, IL-8 or TNF) in a human to normal orsub-normal levels.

By the term "TNF mediated disease or disease state" is meant any and alldisease states in which TNF plays a role, either by production of TNFitself, or by TNF causing another monokine to be released, such as butnot limited to IL-1, or IL-6. A disease state in which IL-1, forinstance is a major component, and whose production or action, isexacerbated or secreted in response to TNF, would therefore beconsidered a disease stated mediated by TNF.

By the term "cytokine" as used herein is meant any secreted polypeptidethat affects the functions of cells and is a molecule which modulatesinteractions between cells in the immune, inflammatory or hematopoieticresponse. A cytokine includes, but is not limited to, monokines andlymphokines regardless of which cells produce them. For instance; amonokine is generally referred to as being produced and secreted by amononuclear cell, such as a macrophage and/or monocyte but many othercells produce monokines, such as natural killer cells, fibroblasts,basophils, neutraphils, endothelial cells, brain astrocytes, bone marrowstromal cells, epideral keratinocytes, and β-lymphocytes. Lymphokinesare generally referred to as being produced by lymphoctye cells.Examples of cytokines include, but are not limited to, Interleukin-1(IL-1), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α) andTumor Necrosis Factor beta (TNF-β).

By the term "cytokine interfering or cytokine suppresive amount" ismeant an effective amount of a compound of Formula (I) which will, causea decrease in the in ivo levels of the cytokine to normal or sub-normallevels, when given to the patient for the prophylaxis or therapeutictreatment of a disease state which is exacerbated by, or caused by,excessive or unregulated cytokine production.

As used herein, the cytokine refered to in the phrase "inhibition of acytokine, for use in the treatment of an HIV infected human" is acytokine which is implicated in (a) the initiation and/or maintenance ofT cell activation and/or activated T cell-mediated HIV gene expressionand/or replication, and/or (b) any cytokine-mediated disease associatedproblem such as cachexia or muscle degeneration.

As TNF-β (also known as lymphotoxin) has close structural homology withTNF-α (also known as cachectin) and since each induces similar biologicresponses and binds to the same cellular receptor, both TNF-α and TNF-βare inhibited by the compounds of the present invention and thus areherein referred to collectively as "TNF" unless specifically delineatedotherwise.

The compounds of the present invention may contain one or moreasymmetric carbon atoms and may exist in racemic and optically activeforms. All of these compounds are contemplated to be within the scope ofthe present invention.

Exemplified compounds of Formula (I) are:

1-(4-pyridyl)-2-(4-fluorophenyl)-4-phenylimidazole;

1-(4-pyridyl)-2-(4-fluorophenyl)-4-(4-hydroxyphenyl)imidazole;

1-(4-pyridyl)-2-(4-fluorophenyl)-4-(4-thiomethylphenyl)imidazole;

1-(4-pyridyl)-2-(4-fluorophenyl)-4-(4-methylsulfinylphenyl)imidazole;

1-(4-pyridyl)-2-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)imidazole;

1-(4-pyridyl)-2-(4-fluorophenyl)-4-methylimidazole;

1-(4-pyridyl)-2-(4-N,N-dimethylaminomethylphenyl)imidazole;

1-(4-pyridyl)-2-(4-fluorophenyl)-4-(benzyloxy)imidazole;

1-(2-methyl-4-pyridyl)-4-(4-methylsulfinylphenyl)imidazole;

1-(2-methyl-4-pyridyl)-4-(4-thiomethylphenyl)imidazole; or

1-(2-methyl-4-pyridyl)4-(3-chlorophenyl)imidazole.

METHODS OF PREPARATION

Preparation of the compounds of Formula (I) can be carried out by one ofskill in the art according to the procedures outlined in the Examples,infra. The preparation of any remaining compounds of Formula (I) notdescribed therein may be prepared by the analogous processes disclosedherein. ##STR3##

Scheme I

Compounds of this invention (wherein r is 0, and s is 1) may be preparedstarting from the α-amino esters or nitriles 1 (illustrated in Scheme 1for an aryl compound, but the method is also applicable to alkyl α-aminoesters or nitriles). Compounds 1 are readily available from thecorresponding aldehyde using the Strecker procedure or other standardmethods. Acylation of 1 with an acid chloride affords the amides 2,which are converted to the aldehyde amides, 3, either directly byreduction with the appropriate hydride-based reagent, for example whenZ═CN or CO₂ R by reduction with diisobutylaluminum hydride (DIBAL), orfor Z═CO₂ R by first reduction of the ester to the alcohol, followed bysubsequent oxidation back to the aldehyde oxidation state of compound 3.Alternatively, in some cases it may be more convenient to begin withcompound 1 as the protected alcohol or aldehyde Z ═CH₂ OR or CH(OR)₂ !and subsequently deprotect and oxidize if needed to prepare 3 followingthe initial acylation step (1 to 2). Reaction of 3 with the requiredamino heterocycle (R₁ term) using acidic catalysis affords compound 4.The R_(2') moiety represents the generic substitution terms as used forthe R_(2') moiety in formula (I). The R_(2') and Y substituent groupsare suitably unreactive moieties under the conditions noted above.Reactive substituent groups, such as the S(O)_(m) moiety of R_(2') underconditions when Z is CO₂ R and the Collins reaction is used, etc., arereadily obvious to one skilled in the art. ##STR4##

Scheme II

An additional method of imidazole synthesis utilizes the amides 5prepared from readily available starting materials using standardcoupling chemistry, such as that employed for the synthesis of pedtides(Scheme II). In addition more vigorous methods such as the reaction ofthe ester or acid of the acyl partner and the appropriate heterocyclicamine (for the example in Scheme II, 4-aminopyridine) at elevatedtemperatures 100°-300° C. with or without a solvent may be used toprepare 5. Conversion of 5 to the imidoyl halide 6 followed by reactionwith an α-amino nitrile (available as the initial product of theStrecker synthesis used in Scheme I) produces the amidine of structure7. Reduction of the nitrile with a metal hydride reducing agent,preferably diisobutylaluminum hydride (DIBAL), affords the intermediateimine which can be cyclized, preferably with acid in a subsequent stepto afford 8. ##STR5##

Scheme III

Condensation of the imidoyl halide 6 (illustrated in scheme II) may alsobe performed with an aziridine to form the amidine derivative 9 (SchemeIII). Reaction of 9 with an alkili halide in an appropriate solvent,preferably NaI in acetone yields the intermediate dihydroimidazole 10which can be dehydrogenated by heating 10 in an inert solvent with avariety of metal catalysis or by oxidation, preferably using BaMnO₄ toproduce the imidazole 8.

If a 2-carboalkoxy aziridine is used, for example 2-carboethoxyaziridine, the resulting imidazole with R₃ ═CO₂ Et can be prepared.Basic hydrolysis (NaOH) of the ester affords the carboxylic acid whichmay be converted to the acid chloride by treatment with oxalyl chloride.Treatment of the acid chloride with an amine affords an amide, or with ametal azide affords the acyl azide. Thermal Beckman rearrangement of theacyl azide yeilds the isocyanate R₃ ═--NCO, which can be reacted witheither oxygen, nitrogen or sulfur nucleophiles to produce thecorresponding carbamate, urea, or thiocarbamate, respectively.Alternatively, the Hunsdieker reaction (treatment of the silver salt ofthe carboxylic acid with bromine) or variations thereof may be used toconvert the acid to the rearranged bromide, R₃ ═Br. Transmetalation ofthe bromide to the ogranolithium, using either n- or t-butyl lithium inan ethereal solvent, followed by addition of a dialkylphosphorochloridate, such as dimethyl chlorophosphate, may be used toprepare the phosphonate ester, R₃ ═P(═O)(OR)₂.

In Schemes I, II, and III the R₃ and Y terms may be an appropriatelyprotected alcohol for example in Scheme III a silyl ether, such ast-butyldimethyl or t-butyldiphenyl, and in Schemes I and II an alkylether, such as methyl connected by an alkyl chain of variable link,(C(R₁₀)₂)_(n) R₃ /Y. Following cyclization to the imidazole the alcoholis deprotected using standard reaction conditions to afford the freealcohol. The alcohol may be oxidized to the carboxylic acid (chromicacid or pryidimium dichromate in dimethyl formamide) and subequentlyconverted to the ester (acid catalysis in the precence of an alcohol orcarbonyl diimidazole followed addition of a basic solution of thealcohol). The alcohol may also be oxidized to the aldehyde (Swern'sreagent or pyridinium chlorochromate in methylene chloride) andcondensed with NH₃, or a primary or secondary amine in the presence ofNaCNBH₃, the Botch reductive amination procedure, to prepare thecorresponding primary, secondary and tertiary amines, respectively.Alternatively the alcohol may be activated for displacement by eithernitrogen, sulfur or phospohorus nucleophiles. For example, reaction ofthe alcohol with diisopropyl azodicarboxylate, triphenyl phosphine, andthioacetic add produces the corresponding thioester which can behydrolized to the thiol and oxidized to the sulfonic acid.

Additional derivatives which may be prepared from the above compoundsare: C(O)NR₈ R₉ from the --CO₂ CH₃ by heating with or without catalyticmetal cyanide, e.g. NaCN, and HNNR₈ R₉ in CH₃ OH; --OC(O)R₈ from the--OH with e.g., ClC(O)R₈ in pyridine; --NR₁₀ --C(S)NR₈ R₉ from --NHR₁₀with an alkylisothiocyante or thiocyanic acid; NR₆ C(O)OR₆ from --NHR₆with the alkyl chloroformate; --NR₁₀ C(O)NR₈ R₉ from the --NHR₁₀ bytreatment with an isocyanate, e.g. HN═C═O or R₁₀ N═C═O; --NR₁₀ --C(O)R₈from the --NHR₁₀ by treatment with Cl--C(O)R₈ in pyridine; --C(═NR₁₀)NR₈R₉ from --C(NR₈ R₉)SR₈ with H₃ NR8⁺ OAc⁻ by heating in alcohol; --C(NR₈R₉)SR₈ from --C(S)NR₈ R₉ with R₆ --I in an inert solvent, e.g. acetone;--C(S)NR₈ R₉ where R₈ or R₉ is not hydrogen from C(S)NH₂ with HNR₈ R₉,C(═NCN)--NR₈ R₉ from --C(═NR₈ R₉)--SR₈ with NH₂ CN by heating inanhydrous alcohol, alternatively from C(═NH)--NR₈ R₉ by treatment withBr--CN and NaEtO-- in EtOH; NR₁₀ --C(═NCN)SR₈ from NHR₁₀ by treatmentwith (R₈ S)₂ C═NCN; --NR₁₀ SO₂ R₈ from NHR₁₀ by treatment with ClSO₂ R₈by heating in pyridine; --NR₁₀ C(S)R₈ from --NR₁₀ C(O)R₈ by treatmentwith Lawesson's reagent2,4-bis(4-methoxyphenyl-1,3,2,4-dithiadiphosphetane-2,4-disulfide!;--NR₁₀ SO₂ CF₃ from NHR₆ with triflic anhydride and base; NR₁₀C(O)--C(O)--OR₈ from --NHR₁₀ with, e.g. methyloxalyl chloride and a basesuch as triethylamine; --NR₁₀ C(O)--C(O)--NR₈ R₉ from --NR₁₀C(O)--C(O)--OR₈ with HNR₈ R₇₉ ; 1-(NR₁₀)-2-imidazolyl from --C(═NH)NHR₁₀by heating with 2-chloroacetaldehyde in chloroform.

SYNTHETIC EXAMPLES

The following examples are illustrative and are not limiting of thecompounds of this invention.

EXAMPLE 1 1-(4-Pyridyl)-2-(4-fluorophenyl)-4-phenylimidazole

Ethyl phenylglycine, hydrochloride. To a mixture of phenylglycine (15.00gram (hereinafter g.), 0.1 mole (hereinafter mol)) in EtOH (100miliLiters (hereinafter mL)) was added 20% ethanolic HCl (30 mL). Themixture was heated at reflux for about 20 hours (hereinafter h.), thenallowed to cool. The solvent was removed in vacuo, and the residue wasused without further purification.

N-(4-Fluorobenzoyl)phenylglycine, ethyl ester. To a solution of ethylphenylglycine, hydrochloride (prepared above) in CH₃ CN (60 mL) wereadded 4-fluorobenzoyl chloride (25.4 g, 0.16 mol) and pyridine. Theresulting mixture was stirred at room temperature for about 5.5 h, thenwas partitioned between aqueous NaHCO₃ and EtOAc. The organic extractwas washed successively with 10% aqueous NaOH, 3N HCl and saturatedaqueous NaCl. The solvent was removed in vacuo, and the residue wascrystallized from CH₂ Cl₂ /hexanes to afford the title compound (19 g,63%).

4-Fluoro-N-(2-hydroxy-1-phenyl)ethylbenzamide. To a solution ofN-(4-fluorobenzoyl)phenylglycine, ethyl ester (1.56 g, 5.2 mmol) in THF(15 mL) was added sodium borohydride (0.50 g, 12.9 mmol), followed byMeOH (4.2 mL). The resulting mixture was allowed to stir for about 75min, during which time additional sodium borohydride was added. Themixture was poured into H₂ O and concentrated under reduced pressure.The residue was partitioned between saturated aqueous NaCl and EtOAc.The organic extract was concentrated in vacuo, and the residue waspurified by flash chromatography, eluting with 25% EtOAc/hexanes toafford the tide compound (0.80 g, 60%).

4-Fluoro-N-(2-oxo-1-phenyl)ethylbenzamide. To a solution of pyridine(1.6 mL, 19.30 mmol) in CH₂ Cl₂ (18 mL) was added, portionwise, CrO₃(1.16 g, 11.58 mmol). Upon completion of the addition, the mixture wasallowed to stir for about 30 min, at which time was added a solution of4-fluoro-N-(2-hydroxy-1-phenyl)ethylbenzamide (0.50 g, 1.93 mmol) in CH₂Cl₂ (35 mL). The resulting mixture was allowed to stir for about 5 min,then was filtered through a pad of florisil and concentrated underreduced pressure to afford the title compound.

1-(4-Pyridyl)-2-(4-fluorophenyl)-4-phenylimidazole. To a solutioncontaining 4-fluoro-N-(2-oxo-1-phenyl)ethylbenzamide (0.15 g, 0.58 mmol)and 4-aminopyridine (0.06 g, 0.65 mmol) in toluene (10 mL) was addedp-toluenesulfonic acid (0.22 g, 1.20 mmol). The mixture was heated atreflux with azeotropic removal of H₂ O. After heating at reflux forabout 1 h, the mixture was allowed to cool and was partitioned betweenaqueous NaHCO₃ and EtOAc. The organic extract was concentrated underreduced pressure and purified by flash chromatography, eluting with asolvent gradient of 1:5 to 1:1 EtOAc/hexanes. The title compound wasobtained (0.04 g, 17%) as a light yellow solid. m.p. 90°-92° C.

EXAMPLE 2 1-(4-Pyridyl)-2-(4-fluorophenyl)-4-(4-hydroxyphenyl)imidazole

Ethyl 4-hydroxyphenylglycine, hydrochloride. To a suspension of4-hydroxyphenylglycine (18.00 g, 0.11 mol) in EtOH (100 mL) was added20% ethanolic HCl (30 mL). The mixture was heated at reflux for 14 h,then was allowed to cool and was concentrated under reduced pressure.The residue was partitioned between saturated aqueous NaHCO₃ and EtOAc,and the organic extract was concentrated in vacuo to afford the tidecompound (15.00 g, 70%).

N-(4-Fluorobenzoyl)-2- 4-oxy-(4-fluorobenzoyl)phenyl)glycine, ethylester. To a suspension of ethyl 4-hydroxyphenylglycine, hydrochloride(prepared above) in CH₃ CN were added 4-fluorobenzoyl chloride (20 mL,0. 17 mol) and pyridine (15.5 mL, 0.20 mol). The resulting mixture wasstirred at room temperature for 5 min, then was partitioned betweenaqueous NaHCO₃ and EtOAc. The organic extract was washed successivelywith 3N HCl, saturated aqueous NaCl, 5% aqueous NaHCO₃ and saturatedaqueous NaCl. The solvent was removed in vacuo to afford the titlecompound.

4-Fluoro-N- 1-(4-hydroxyphenyl-2-hydroxy)ethyl!benzamide. To a solutionof N-(4-fluorobenzoyl)-2- 4-oxy-(4-fluorobenzoyl)phenyl!glycine, ethylester (1.00 g, 2.27 mmol) in THF (6 mL) was added sodium borohydride(0.22 g, 5.70 mmol). The mixture was warmed to 55° C. and MeOH (1.9 mL)was added over 10 min.

Upon completion of the addition, the mixture was poured into H₂ O andconcentrated under reduced pressure. The residue was partitioned betweensaturated aqueous NaCl and EtOAc. The organic extract was concentratedin vacuo, and the residue was purified by flash chromatography, elutingwith 1:1 EtOAc/hexanes to afford the title compound (0.46 g, 73%).

N- 1-(4-Benzyloxyphenyl-2-hydroxy!ethyl!-4-fluorobenzamide. To asolution of 4-fluoro-N- 1-(4-hydroxyphenyl-2-hydroxy)ethyl!benzamide(0.40 g, 1.45 mmol) in acetone were added potassium carbonate (0.30 g,2.18 mmol) and benzyl bromide (0.29 g, 1.75 mmol). The resulting mixturewas heated at reflux for 20 h, then was allowed to cool and wasconcentrated under reduced pressure. The residue was purified by flashchromatography, eluting with 1:1 EtOAc/hexanes to afford the titlecompound (0.50 g, 94%).

N- 1-(4-Benzyloxyphenyl-2-oxo)ethyl!-4-fluorobenzamide. To a solution ofpyridine (1.1 mL, 12.8 mmol) in CH₂ Cl₂ (10 mL) was added, portionwise,CrO₃ (0.78 g, 7.73 mmol). Upon completion of the addition, the mixturewas allowed to stir for 30 min, at which time was added a solution of N-1-(4-benzyloxyphenyl-2-hydroxy)ethyl!-4-fluorobenzamide (0.47 g, 1.28mmol) in CH₂ Cl₂ (35 mL). The resulting mixture was allowed to stir for25 min, then was filtered through a pad of florisil and concentratedunder reduced pressure to afford the title compound.

1-(4-Pyridyl)-2-(4-fluorophenyl)-4-(4-benzyloxyphenyl)imidazole. To asolution containing N-1-(4-benzyloxyphenyl-2-oxo)ethyl!-4-fluorobenzamide (0.38 g, 1.00 mmol)and 4-aminopyridine (0.11 g, 1.17 mmol) in toluene was addedp-toluenesulfonic acid (0.42 g, 2.20 mmol). The mixture was heated atreflux with azeotropic removal of H₂ O. After heating at reflux for 1 h,the mixture was allowed to cool and was partitioned between aqueousNaHCO₃ and EtOAc. The organic extract was concentrated under reducedpressure and purified by flash chromatography, eluting with a solventgradient of 1:5 to 1:2 EtOAc/hexanes. The title compound was obtained(0.06 g, 14%) and was crystallized from EtOAc/hexanes.

1-(4-Pyridyl)-2-(4-fluorophenyl)-4-(4-hydroxyphenyl)imidazole. A mixturecontaining1-(4-pyridyl)-2-(4-fluorophenyl)-4-(4-benzyloxyphenyl)imidazole (0.13 g,0.3 mmol) and 10% palladium on activated carbon (100 mg) in EtOAc wasstirred under an atmosphere of H₂ for 10 h, at which time the reactionmixture was filtered through a pad of Celite. The filtrate wasconcentrated under reduced pressure, and the residue was purified byflash chromatography, eluting with 1:1 EtOAc/hexanes.

The material which was isolated was crystallized from EtOAc/hexanes toafford the title compound (0.07 g, 70%). m.p. 230°-231° C.

EXAMPLE 3

1-(4-Pyridyl)-2-(4-fluorophenyl)-4-(4-thiomethylphenyl) imidazole. Thecompound of Example 3 was produced by the process according to Scheme I;converting 4-thiomethylbenzaldehyde to the amino nitrile and condensingthis with 4-fluorobenzoyl chloride. Reduction of the nitrile to thealdehyde was followed by condesation with 4-amino pyridine according tothe method of examples 1 and 2 to afford the title compound, m.p.192°-196° C.

EXAMPLE 4

1-(4-Pyridyl)-2-(4-fluorophenyl)-4-(4-methylsulfinylphenyl) imidazole.Oxidation of 1-(4-pyridyl)-2-(4-fluorophenyl)-4-(4-thiomethylphenyl)imidazole of Example 3 with K₂ S₂ O₈ in acetic acid followed bychromatography on silica and recrystallization afforded the titledsulfoxide, m.p. 201°-203° C.

EXAMPLE 5

1-4-pyridyl)-2-(4-fluorophenyl)-4-methylimidazole. The compound ofExample 5 was produced by the process according to Scheme III, employingmethyl aziridine and the imidoyl chloride prepared from the amide formedby condensation of 4-amino pyridine and 4-fluorobenzoyl chloride.Cyclization and dehydrogenation of this adduct affords the titleimidazole as a white solid, m/e (rel. int.): 254 (M+H)⁺ !.

EXAMPLE 6

1-(2-methylpyrid-4-yl)-2-(4-fluororphenyl)-4-(4-thiomethylphenyl)imidazole.This compound was produced by the process according to Scheme I;converting 4-thiomethylbenzaldehyde to the amino nitrite and condensingthis with 4-fluorobenzoyl chloride. Reduction of the nitrile to thealdehyde was followed by condensation with 2-methyl-4-amino pyridineaccording to the method of Examples 1 and 2 to afford the titlecompound, m.p. 144°-146° C.

EXAMPLE 7

1-(2-methylpyrid-4-yl)-2-(4-fluorophenyl)-4-(4-methylsulfinylphenyl)imidazole.Oxidation of1-(2-methylpyrid-4-yl)-2-(4-fluorophenyl)-4-(4-thiomethylphenyl)imidazoleof Example 7 with K₂ S₂ O₈ in acetic acid followed by chromatography onsilica and recrystallization afforded the titled sulfoxide, m.p.160°-163° C.

By analogous methods to those described above in Example 1 to 7, and inSchemes I to III herein the following compounds may be produced:

Example 8--1-(4-pyridyl)-2-(4-N,N-dimethylaminomethylphenyl)imidazole.

Example 9--1-(4-pyridyl)-2-(4-fluorophenyl)4-(benzyloxy) imidazole.

Example 10--1-(2-methyl-4-pyridyl)-4-(3-chlorophenyl)imidazole.

METHODS OF TREATMENT

The compounds of Formula (I) can be used in the manufacture of amedicament for the prophylactic or therapeutic treatment of any diseasestate in a human, or other mammal, which is exacerbated or caused byexcessive or unregulated excessive or unregulated cytokine production,more specifically IL-1, IL-8 or TNF production, by such mammal's cell,such as but not limited to monocytes and/or macrophages.

Compounds of Formula (I) are capable of inhibiting proinflammatorycytokines, such as IL-1, IL-8 and TNF and are therefore of use intherapy. IL- 1, IL-8 and TNF affect a wide variety of cells and tissuesand these cytokines, as well as other luekocyte derived cytokines, areimportant and critical inflammatory meditators of a wide variety ofdisease states and conditions. The inhibition of these pro-inflammatorycytokines is of benefit in controlling, reducing and alleviating many ofthese diseases.

The compounds of Formula (I) are administered in an mount sufficient toinhibit TNF production such that it is regulated down to normal levels,or in some case to subnormal levels, so as to ameliorate or prevent thedisease state. Abnormal levels of TNF, for the present invention,constitute levels of 1) free (not cell bound) TNF, greater than or equalto 1 picogram per ml; 2) any cell associated TNF; or 3) the presence ofTNF mRNA above basal levels in cells or tissues in which TNF isproduced.

The compounds of Formula (I) may be used in the treatment of any diseasestates mediated by excessive or unregulated TNF production, such as butnot limited to rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions; sepsis,septic shock, endotoxic shock, gram negative sepsis, toxic shocksyndrome, adult respiratory distress syndrome, cerebral malaria, chronicpulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, boneresorption diseases, such as osteoporosis, reperfusion injury, graft vs.host reaction, allograft rejections, fever and myalgias due toinfection, such as influenza, cachexia secondary to infection ormalignancy, cachexia, secondary to acquired immune deficiency syndrome(AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissueformation, Crohn's disease, ulcerative colitis, pyresis, AIDS and otherviral infections, such as cytomegalia virus (CMV), influenza virus, andthe herpes family of viruses such as Herpres Zoster or Simplex I and II.

The compounds of Formula (I) may also be used topically as well in thetreatment or prophylaxis of inflammatory topical disease states mediatedor exacerbated by excessive TNF production respectively, such as forrheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, goutyarthritis and other arthritic conditions, inflamed joints, eczema,psoriasis or other inflammatory skin conditions such as sunburn;inflammatory eye conditions including conjunctivitis; pyresis, pain andother conditions associated with inflammation.

The compounds of Formula (I) may also be used in association with theveterinary field for treatment of TNF mediated diseases such as vitalinfections. Examples of such viruses include but are not limited to,feline immunodeficiency virus (FIV) or other retroviral infection suchas equine infectious anaemia virus, caprine arthritis virus, visnavirus, maedi virus and other lentiviruses.

Interleukin-1 (IL-1) has been demonstrated to mediate a variety ofbiological activities thought to be important in immunoregulation andother physiological conditions such as inflammation See, e.g., Dinarelloet al., Rev. Infect Disease. 6, 51 (1984)!. The myriad of knownbiological activities of IL-1 include the activation of T helper cells,induction of fever, stimulation of prostaglandin or collagenaseproduction, neutrophil chemotaxis, induction of acute phase proteins andthe suppression of plasma iron levels.

The discovery that the compounds of Formulas (I) are inhibitors ofcytokines, specifically IL-1 is based upon the effects of the compoundsof Formulas (I) on the production of the IL-1 in vitro, on the humanmonocyte, the assays of which are described herein.

There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease.These include rheumatoid arthritis, osteoarthritis, endotoxemia and/ortoxic shock syndrome, other acute or chronic inflammatory disease statessuch as the inflammatory reaction induced by endotoxin or inflammatorybowel disease; tuberculosis, atherosclerosis, muscle degeneration,cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis,gout, traumatic arthritis, rubella arthritis, and acute synovitis.Recent evidence also links IL-1 activity to diabetes and pancreatic βcells.

Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985), reviews thebiological activities which have been attributed to IL-1. It should benoted that some of these effects have been described by others asindirect effects of IL-1.

The compounds of Formula (I) have also been shown to inhibit theproduction of Interleukin-8 (NAP-1/IL-8). IL-8 is a chemotactic factorfirst identified and characterized in 1987. Il-8 is produced by severalcell types including mononuclear cells, fibroblasts, endothelial cells,and keratinocytes. Many different names have been applied to IL-8, suchas neutrophil attractor/activation protein-1 (NAP-1), monocyte derivedneutrophil chemotactic factor (MDNCF), neutrophil activating factor(NAF), and T-cell lymphocyte chemotactic factor.

There are many disease states in which excessive or unregulated IL-8production is implicated in exacerbating and/or causing the disease.These diseases are characterized by massive neutrophil infiltration suchas, psoriasis, inflammatory bowel disease, asthma, cardiac and renalreperfusion injury, adult respiratory distress syndrome, thrombosis andglomerulonephritis. All of these diseases have the association ofincreased IL-8 production, which is responsible for the chemotaxis ofneutrophils into the inflammatory site. In contrast to otherinflammatory cytokines (IL-1, TNF, and IL-6) IL-8 has the uniqueproperty of promoting neutrophil chemotaxis. Therefore, the inhibitionof IL-8 production would lead to a direct reduction in the neutrophilinfiltration.

The discovery of a compound which specifically inhibits IL-1, IL-8, andTNF production win not only contribute to the understanding of how thismolecule is synthesized, processed and secreted, but will also provide atherapeutic approach for diseases in which excessive or unregulated IL-1and TNF production is implicated.

PHARMACEUTICAL COMPOSITIONS

In order to use a compound of the Formula (I) or a pharmaceuticallyacceptable salt thereof for the treatment of humans and other mammals itis normally formulated in accordance with standard pharmaceuticalpractice as a pharmaceutical composition.

This invention, therefore, also relates to a pharmaceutical compositioncomprising an effective, non-toxic amount of a compound of Formulas (I)and a pharmaceutically acceptable carrier or diluent. The compounds ofFormula (I) are administered in conventional dosage forms prepared bycombining a compound of Formula (I) with standard pharmaceuticalcarriers according to conventional procedures. The compounds of Formula(I) may also be administered in conventional dosages in combination witha known, second therapeutically active compound. These procedures mayinvolve mixing, granulating and compressing or dissolving theingredients as appropriate to the desired preparation.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like. Similarly, the carrier or diluent may includetime delay material well known to the art, such as glycerylmono-stearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 g. When a liquid carrier is used,the preparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule or nonaqueousliquid suspension.

The compounds of Formula (I) may be administered topically. Thus, thecompounds of Formula (I) may be administered topically in the treatmentor prophylaxis of inflammation or other cytokine related diseases in amammal, such as rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions, inflamedjoints, eczema, psoriasis or other inflammatory skin conditions such assunburn; inflammatory eye conditions including conjunctivitis; pyresis,pain and other conditions associated with inflammation.

The amount of a compound of Formula (I), for all methods of usedisclosed herein, required for therapeutic effect on topicaladministration will, of course, vary with the compound chosen, thenature and severity of the inflammatory condition, whether eicosanoid orcytokine mediated, and the animal undergoing treatment, and isultimately at the discretion of the physician. A suitable, topical,anti-inflammatory dose of an active ingredient, i.e., a compound ofFormula (I) is 0.1 mg to 150 mg, administered one to four, preferablytwo or three times daily.

By topical administration is meant non-systemic administration andincludes the application of a compound of Formula (I) externally to theepidermis, to the buccal cavity and instillation of such a compound intothe ear, eye and nose, and where the compound does not significantlyenter the blood stream. By systemic administration is meant oral,intravenous, intraperitoneal and intramuscular administration.

While it is possible for an active ingredient to be administered aloneas the raw chemical, it is preferable to present it as a pharmaceuticalformulation. The active ingredient may comprise, for topicaladministration, from 0.001% to 10% w/w, e.g. from 1% to 2% by weight ofthe formulation although it may comprise as much as 10% w/w butpreferably not in excess of 5% w/w and more preferably from 0.1% to 1%w/w of the formulation.

The topical formulations of the present invention comprise an activeingredient together with one or more acceptable carrier(s) therefor andoptionally any other therapeutic ingredient(s). The carrier(s) must be`acceptable` in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as liniments, lotions, creams, ointmentsor pastes, and drops suitable for administration to the eye, ear ornose.

Drops according to the present invention may comprise sterile aqueous oroily solutions or suspensions and may be prepared by dissolving theactive ingredient in a suitable aqueous solution of a bactericidaland/or fungicidal agent and/or any other suitable preservative, andpreferably including a surface active agent. The resulting solution maythen be clarified by filtration, transferred to a suitable containerwhich is then sealed and sterilized by autoclaving or maintaining at98°-100° C. for half an hour. Alternatively, the solution may besterilized by filtration and transferred to the container by an aseptictechnique. Examples of bactericidal and fungicidal agents suitable forinclusion in the drops are phenylmercuric nitrate or acetate (0.002%),benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).Suitable solvents for the preparation of an oily solution includeglycerol, diluted alcohol and propylene glycol.

Lotions according to the present invention include those suitable forapplication to the skin or eye. An eye lotion may comprise a sterileaqueous solution optionally containing a bactericide and may be preparedby methods similar to those for the preparation of drops. Lotions orliniments for application to the skin may also include an agent tohasten drying and to cool the skin, such as an alcohol or acetone,and/or a moisturizer such as glycerol or an oil such as castor oil orarachis oil.

Creams, ointments or pastes according to the present invention aresemi-solid formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient infinely-divided or powdered form, alone or in solution or suspension inan aqueous or non-aqueous fluid, with the aid of suitable machinery,with a greasy or non-greasy basis. The basis may comprise hydrocarbonssuch as hard, soft or liquid paraffin, glycerol, beeswax, a metallicsoap; a mucilage; an oil of natural origin such as almond, corn,arachis, castor or olive oil; wool fat or its derivatives, or a fattyacid such as steric or oleic acid together with an alcohol such aspropylene glycol or macrogels. The formulation may incorporate anysuitable surface active agent such as an anionic, cationic or non-ionicsurfactant such as sorbitan esters or polyoxyethylene derivativesthereof. Suspending agents such as natural gums, cellulose derivativesor inorganic materials such as silicaceous silicas, and otheringredients such as lanolin, may also be included.

The methods of the subject invention may be carried out by deliveringthe monokine activity interfering agent parenterally. The term`parenteral` as used herein includes intravenous, intramuscular,subcutaneous intranasal, intrarectal, intravaginal or intraparitonealadministration. The subcutaneous and intramuscular forms of parenteraladministration are generally preferred. Appropriate dosage forms forsuch administration may be prepared by conventional techniques.

For all methods of use disclosed herein for the compounds of Formulas(I), the daily oral dosage regimen will preferably be from about 0.05 toabout 80 mg/kilogram of total body weight, preferably from about 0.1 to30 mg/kg, more preferably from about 0.5 mg to 15 mg. The dailyparenteral dosage regimen will preferably be from about 0.05 to about 80mg per kilogram (kg) of total body weight, preferably from about 0. 1 toabout 30 mg/kg, and more preferably from about 0.5 mg to 15 mg/kg.

The compounds of Formula (I) may also be administered by inhalation. By"inhalation" is meant intranasal and oral inhalation administration.Appropriate dosage forms for such administration; such as an aerosolformulation or a metered dose inhaler, may be prepared by conventionaltechniques. The preferred daily dosage amount of a compound of Formula(I) administered by inhalation for all methods disclosed herein, is fromabout 0.01 mg/kg to about 1 mg/kg per day.

It will be recognized by one of skill in the art that the form andcharacter of the pharmaceutically acceptable carrier or diluent isdictated by the amount of active ingredient with which it is to becombined, the route of administration and other well-known variables.

It will also be recognized by one of skill in the art that the optimalquantity and spacing of individual dosages of a compound of Formula (I)or a pharmaceutically acceptable salt thereof will be determined by thenature and extent of the condition being treated, the form, route andsite of administration, and the particular patient being treated, andthat such optimums can be determined by conventional techniques.

It will also be appreciated by one of skill in the art that the optimalcourse of treatment, i.e., the number of doses of a compound of Formula(I) or a pharmaceutically acceptable salt thereof given per day for adefined number of days, can be ascertained by those skilled in the artusing conventional course of treatment determination tests.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following Examples are, therefore, to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way.

EXAMPLE A Inhibitory Effect of Compounds of Formula (I) on in vitro IL-1Production by Human Monocytes

The effects of compounds of Formula (I) on the in vitro production ofIL-1 by human monocytes was examined using the following protocol.

Bacterial lipopolysaccharide (LPS) was used to induce IL-1 production byhuman peripheral blood monocytes. IL-1 activity was measured by itsability to stimulate a Interleukin 2 (IL-2) producing cell line (EL-4)to secrete IL-2, in concert with A23187 ionophore, according to themethod of Simon et al., J. Immunol. Methods, 84, 85, (1985). Humanperipheral blood monocytes were isolated and purified from either freshblood preparations from volunteer donors, or from blood bank buffycoats, according to the procedure of Colotta et al., J. Immunol., 132,936 (1984). 1×10⁶ of such monocytes were plated in 24-well plates at aconcentration of 1-2 million/ml per well. The cells were allowed toadhere for 2 hours, after which time non-adherent cells were removed bygentle washing. Test compounds were then added to the cells for 1 hour(hr) before the addition of lipopolysaccharide (50 ng/ml), and thecultures were incubated at 37° C. for an additional 24 hours. At the endof the incubation period, culture supernatants were removed andclarified of cells and all debris. Culture supernatants were immediatelyassayed for IL-1 biological activity in the manner described above, aswell as for prostaglandin and/or leukotriene concentrations byradioimmunoassay.

The compounds of Formula (I), Examples 1, 2, and 5 are potent inhibitorsof in vitro IL-1 production by human monocytes having IC₅₀ 's between0.1 μM and 5 μM. The compounds of Examples 3, and 4 exhibited an IC₅₀of >5 μM.

Based on the widely held belief of the role of unmodulated (i.e.,excessive) in vivo IL1 production in causing or aggravating inflammatoryresponses and other disease states (see, e.g., Fontana et al., supra;Wood et al., supra; Akejima and Dinarello, supra; Habicht and Beck,supra; Chesque et al., supra; Benjamin et al., supra; and Dinarello,supra), and based on the fact that compounds of Formula (I) inhibit invitro IL-1 production by human macrophages and/or monocytes, thecompounds of Formula (I) will inhibit the in vivo IL-1 production bymonocytes and/or macrophages in a human in need thereof when usedaccording to the method of the subject invention.

UTILITY EXAMPLE B Inhibitory Effect of Compounds of Formula (I) on invitro TNF Production by Human Monocytes

Section I: Assay Set-up

The effects of compounds of Formula (I) on the in vitro production ofTNF by human monocytes was examined using the following protocol.

Human peripheral blood monocytes were isolated and purified from eitherblood bank buffy coats or plateletpheresis residues, according to theprocedure of Colotta, R. et al., J. Immunol., 132(2):936 (1984). Themonocytes were plated at a density of 1×10⁶ cells/ml medium/well in24-well multi-dishes. The cells were allowed to adhere for 1 hour afterwhich time the supernatant was aspirated and 1 ml fresh medium(RPMI-1640 (Whitaker Biomedical Products, Whitaker, Calif.) containing1% fetal calf serum and penicillin and streptomycin at 10 units/ml wasadded. The cells were incubated for 45 minutes in the presence orabsence of test compounds at 1 nM-10 μM dose ranges (compounds weresolubilized in Dimethylsulfoxide/Ethanol such that the final solventconcentration in the culture medium was 0.5% Dimethyl sulfoxide/0.5%Ethanol). Bacterial lipopolysaccharide (E. coli 055:B5 LPS! from SigmaChemicals Co.) was then added at 100 ng/ml in 10 ml Phosphate BufferedSaline (PBS) and cultures incubated for 16-18 hours at 37° C. in a 5%CO₂ incubator. At the end of the incubation period, culture supernatantswere removed from the cells, centrifuged at 3000 revolutions per minute(rpm) to remove cell debris and 0.05 ml of the supernatant assayed forTNF activity using the radioimmunoassay described below.

Section II: Radioimmunoassay Procedure for TNF Activity

The assay buffer consisted of 0.01M NaPO₄, 0.15M NaCl, 0.025M EDTA and0.1% sodium azide at pH 7.4. Human recombinant TNF (rhTNF) obtainedusing the procedure of Chen et al., Nature, 330:581-583 (1987) wasiodinated by a modified Chloramine-T method described in Section IIIbelow. To samples (50 μl culture supernatants) or rhTNF standards, a1/9000 dilution of polyclonal rabbit anti-rhTNF (Genzyme, Boston, Mass.)and 8000 cpm of ¹²⁵ I-TNF was added in a final volume of 400 μl bufferand incubated overnight (18 hours) at 4° C. Normal rabbit serum and goatanti-rabbit IgG (Calbiochem) were titrated against each other formaximum precipitation of the anti-rhTNF. The appropriate dilutions ofcarrier normal rabbit serum (1/200), goat anti-rabbit IgG (1/4) and 25Units heparin (Calbiochem) were allowed to precipitate and 200 gl ofthis complex was added per assay tube and incubated overnight at 4° C.Tubes were centrifuged for 30 minutes at 2000 rpm, supernatants werecarefully aspirated, and radioactivity associated with the pelletsmeasured in a Beckman Gamma 5500 counter. The logit-log lineartransformation curve was used for the calculations. The concentrationsof TNF in the samples was read of a standard curve of rhTNF that waslinear in the 157 to 20,000 pg/ml range.

Section III: Radioiodination of rhTNF

Iodination of rhTNF was performed using a modified chloramine-T methodof Frolik et al., J. Biol. Chem., 259:10995-11000 (1984). Briefly, 5 mgof rhTNF in 5 ml of 20 MM Tris ph 7.5, was diluted with 15 ml of 0.5MKPO₄ and 10 ml of carrier free ¹²⁵ I(100 mCi/ml;ICN). To initiate thereaction, a 5 ml aliquot of a 100 mg/ml (aqueous) chloramine-T solutionwas added. After 2 minutes at room temperature, an additional 5 mlaliquot was added followed 1.5 minutes later by a final 5 ml addition ofchloramine-T. The reaction was stopped 1 minute later by sequentialaddition of 20 ml of 50 mM Sodium Metabisulfite, 100 ml of 120 mMPotassium Iodide and 200 ml of 1.2 mg/ml Urea. The contents were mixedand the reaction mixture was passed over a pre-packed Sephadex G-25column (PD 10 Pharmacia), equilibrated and eluted with PhosphateBuffered Saline pH 7.4 containing 0.25% gelatin. The peak radioactivitycontaining fractions were pooled and stored at -20° C. Specific activityof ¹²⁵ I-TNF was 80-100 mCi/mg protein. Biological activity of iodinatedTNF was measured by the L929 cytotoxicity assay of Neale, M. L. et al.,Eur. J. Can. Clin. Oncol., 25(1):133-137 (1989) and was found to be 80%that of unlabeled TNF.

Section IV: Measurement of TNF-ELISA

Levels of TNF were also measured using a modification of the basicsandwich ELISA assay method described in Winston et al., CurrentProtocols in Molecular Biology. Page 11.2.1, Ausubel et al., Ed. (1987)John Wiley and Sons, New York, USA. The ELISA employed a murinemonoclonal anti-human TNF antibody, described below, as the captureantibody and a polyclonal rabbit anti-human TNF, described below, as thesecond antibody. For detection, a peroxidase-conjugated goat anti-rabbitantibody (Boehringer Mannheim, Indianopolis, Ind., USA, Catalog #605222)was added followed by a substrate for peroxidase (1 mg/mlorthophenylenediamine with 0.1% urea peroxide). TNF levels in sampleswere calculated from a standard curve generated with recombinant humanTNF produced in E. Coli (obtained from SmithKline BeechamPharmaceuticals, King of Prussia, Pa., USA).

Section V: Production of Anti-human TNF Antibodies

Monoclonal antibodies to human TNF were prepared from spleens of BALB/cmice immunized with recombinant human TNF using a modification of themethod of Kohler and Millstein, Nature 256:495 (1975), the entiredisclosure of which is hereby incorporated by reference. Polyclonalrabbit anti-human TNF antibodies were prepared by repeated immunizationof New Zealand White (NZW) rabbits with recombinant human TNF emulsifiedin complete Freund's adjuvant (DIFCO, IL., USA).

Results

The compounds of Formula (I), Examples 1 and 2 both demonstrated anIC50's between 0.5 μM and 3.5 μM in the above described assay. The exactmechanism by which any compound of Formula (I) inhibits in vitro TNFproduction by monocytes is not presently known. This inhibitory activitydoes not seem to correlate with the property of any of the compounds ofFormula (I) in mediating arachidonic acid metabolism inhibition sinceother nonsteroidal antiinflammatory drugs with potent cyclooxygenaseand/or lipoxygenase inhibitory activity do not inhibit TNF production atnontoxic doses. Furthermore, the ability of a compound to inhibitproduction of prostaglandin and/or leukotriene synthesis does not meanthat it will necessarily also inhibit TNF production.

EXAMPLE C Inhibitory Effect of Compounds of Formula (I) on IL-8Production

The effects of compounds of Formula (I) on the inhibition of IL-8production from Human Umbilical Vein Endothelial cells is examined usingthe following protocol.

Primary human umbilical cord endothelial cells (HUVEC) are obtained fromCell Systems (Kirland, Wash.) and maintained in culture mediumsupplemented with 15% fetal bovine serum and 1% CS-HBGF consisting ofαFGF and heparin. Cells are then diluted 20-fold before being plated(250 μl) into gelating coated 96-well plates. Prior to use, culturemedium is replaced with fresh medium (200 μl). 25 μl of either buffer ortest compounds at the appropriate concentration is added to each well inquadruplicate wells. This is followed immediately by the addition of 25μl of the compounds of Formula (I) at concentrations between 1-10 μM.The plates are allowed to incubate for the appropriate time, asindicated in a humidified incubator at 37° C. with 5% CO₂. At the end ofthe incubation period, supernatant is removed and assayed for IL-8concentration using an IL-8 ELISA kit obtained from R&D Systems(Minneapolis, Minn.). All data presented is as a mean value (ng/ml) ofmultiple samples based on the standard curve. IC50's where appropriateare generated by non-linear regression analysis.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe are can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore the Examples herein are to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

What is claimed is:
 1. A compound of the formula: ##STR6## wherein R₁ isa mono- or di- substituted 4-pyridyl wherein the substituent isindependently selected from the group consisting of hydrogen, C₁₋₄alkyl, halo, O--C₁₋₄ alkyl, S--C₁₋₄ alkyl, or N(R_(a))₂ ;R_(a) ishydrogen, C₁₋₆ alkyl, or R_(a) may form a heterocyclic ring which ispyrrolidine, piperidine, piperazine, morpholine, imidazolidine, orpyrazolidine; R₂ is mono- or di-substituted phenyl wherein thesubstituents are independently selected from the group consisting ofhydrogen, halo, S(O)_(m) R₅, OR₆, halo substituted C₁₋₄ alkyl, C₁₋₄alkyl, or N(R₁₂)₂ ; R₄ is hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₇ cycloalkyl, or C₅₋₇ cycloalkenyl; R₃ is (X)_(r) --(Q)_(s)--(Y)_(t) ; X is hydrogen, --(C(R₁₀)₂)_(n), --NR₁₃, --O-- or S(O)_(m) ;r is a number having a value of 0 or 1; m is a number having a value of0, 1 or 2; Q is alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl,naphthyl, phenyl C₁₋₁₀ alkyl, or naphthyl C₁₋₁₀ alkyl; s is a numberhaving a value of 0 or 1; Y is a substituent selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl,halogen, --(C(R₁₀)₂)_(n) OR₈, --(C(R₁₀)₂)_(n) NO₂, --(C(R₁₀)₂)_(n)S(O)_(m') R₁₁, --(C(R₁₀)₂)_(n) SR₈, --(C(R₁₀)₂)_(n) S(O)_(m') OR₈,--(C(R₁₀)₂)_(n) S(O)_(m') NR₈ R₉, --X_(a) --P(Z)--(X_(a) R₁₃)2,--(C(R₁₀)₂)_(n) NR₈ R₉, --(C(R₁₀)₂)_(n) CO₂ R₈, --(C(R₁₀)₂)_(n)OC(O)--R₈, --(C(R₁₀)₂)_(n) CN, --(C(R₁₀)₂)_(n) CONR₈ R₉, --(C(R₁₀)₂)_(n)C(S)NR₈ R₉, --(C(R₁₀)₂)_(n) NR₁₀ C(O)R₈, --(C(R₁₀)₂)_(n) NR₁₀ C(S)R₈,--(C(R₁₀)₂)_(n) NR₁₀ C(Z)NR₈ R₉, --(C(R₁₀)₂)_(n) NR₁₀ S(O)_(m) R₁₁,--(C(R₁₀)₂)_(n) NR₁₀ C(═NCN)--S--R₁₁, --(C(R₁₀)₂)_(n) NR₁₀ C(═NCN)--NR₈R₉, --(C(R₁₀)₂)_(n) NR₁₀ C(O)C(O)--NR₈ R₉, --(C(R₁₀)₂)_(n) NR₁₀C(O)C(O)--OR₁₀, --(C(R₁₀)₂)_(n) C(═NR₁₀)--NR₈ R₉, --(C(R₁₀)₂)_(n)--C(═NR₁₀)--ZR₁₁, --(C(R₁₀)₂)_(n) --OC(Z)--NR₈ R₉, --(C(R₁₀)₂)_(n) NR₁₀S(O)_(m) CF₃, or --(C(R₁₀)₂)_(n) NR₁₀ C(O)OR₁₀ ; t is a number having avalue of 0, 1, 2, or 3; X_(a) is independently --(C(R₁₀)₂)_(n), --NR₈--, --O-- or --S--; Z is oxygen or sulfur; m' is a number having a valueof 1 or 2; n is a number having a value of 0 to 10; R₅ is hydrogen, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl,phenyl, naphthyl, or N(R₇)₂ ; provided that when m is 1 or 2 then R₅ isnot hydrogen; R₆ is hydrogen, C₁₋₄ alkyl, halo substituted C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, phenyl,or naphthyl; R₇ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,phenyl, naphthyl, or may form a heterocyclic ring which is pyrrolidine,piperidine, piperazine, morpholine, imidazolidine, or pyrazolidine;provided that when R₅ is N(R₇)₂ then m is 1 or 2; R₈ is hydrogen, C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl,phenyl, naphthyl, phenyl C₁₋₁₀ alkyl, or naphthyl C₁₋₁₀ alkyl; R₉ ishydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl,C₅₋₇ cycloalkenyl, phenyl, naphthyl, phenyl C₁₋₁₀ alkyl, or naphthylC₁₋₁₀ alkyl, or R₈ and R₉ may together form a heterocyclic ring which ispyrrolidine, piperidine, piperazine, morpholine, imidazolidine, orpyrazolidine; R₁₀ is hydrogen, or C₁₋₄ alkyl; R₁₁ is C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cyclo phenyl, naphthyl,phenyl C₁₋₁₀ alkyl, or naphthyl C₁₋₁₀ alkyl; R₁₂ is hydrogen, C₁₋₄alkyl, phenyl, naphthyl, or may form a heterocyclic which ispyrrolidine, piperidine, piperazine, morpholine, imidazolidine, orpyrazolidine; R₁₃ is hydrogen, C₁₋₁₀ alkyl, cycloalkyl; phenyl,naphthyl, phenyl C₁₋₁₀ alkyl, or naphthyl C₁₋₁₀ alkyl; andpharmaceutically acceptable salts thereof.
 2. The compound according toclaim 1 wherein s is
 0. 3. The compound according to claim 2 wherein ris
 0. 4. The compound according to claim 3 wherein Y is alkyl,--(C(R₁₀)₂)_(n) OR₈, --(C(R₁₀ ₁₀)₂)_(n) S(O)_(m') R₁₁, --(C(R₁₀)₂)_(n)SR₈, --(C(R₁₀)₂)_(n) S(O)_(m') OR₈, --(C(R₁₀)₂)_(n) S(O)_(m') NR₈ R₉,--X_(a) --P(Z)--(X_(a) R ₁₃)2, --(C(R₁₀)₂)_(n) NR₈ R₉, --(C(R₁₀)₂)_(n)C(Z)OR₈, --(C(R₁₀)₂)_(n) OC(Z)--R₈, --(C(R₁₀)₂)_(n) C(O)NR₈ R₉,--(C(R₁₀)₂)_(n) NR₁₀ C(═NCN)--NR₈ R₉, or --(C(R₁₀)₂)_(n) NR₁₀ S(O)_(m)R₁₁.
 5. The compound according to claim 4 wherein Y is alkyl,--(C(R₁₀)₂)_(n) OR₈, (CH₂)_(n) S(O)_(m) R₆, (CH₂)_(n) CO₂ R₈,--(C(R₁₀)₂)_(n) NR ₁₀ C(═NCN)--NR₈ R₉, --(C(R₁₀)₂)_(n) NR₈ R₉, or--X_(a) --P(Z)--(X_(a) R₁₃)2 ; and n is 0 to
 4. 6. The compoundaccording to claim 1 wherein s is
 1. 7. The compound according to claim6 wherein Q is phenyl or naphthyl.
 8. The compound according to claim 7wherein Y is alkyl, --(C(R₁₀)₂)_(n) OR₈, --(C(R₁₀)₂)_(n) S(O)_(m') R₁₁,--(C(R₁₀)₂)_(n) SR₈, --(C(R₁₀)₂)_(n) S(O)_(m') OR₈, --(C(R₁₀)₂)_(n)S(O)_(m') NR₈ R₉, --X_(a) --P(Z)--(X_(a) R ₁₃)2, --(C(R₁₀)₂)_(n) NR₈ R₉,--(C(R₁₀)₂)_(n) C(Z)OR₈, --(C(R₁₀)₂)_(n) OC(Z)--R₈, --(C(R₁₀)₂)_(n)C(O)NR₈ R₉, --(C(R₁₀)₂)_(n) NR₁₀ C(═NCN)--NR₈ R₉, or --(C(R₁₀)₂)_(n)NR₁₀ S(O)_(m) R₁₁.
 9. The compound according to claim 7 wherein r is 0,or r is 1 and X is --(C(R₁₀)₂)_(n).
 10. The compound according to claim7 wherein R₄ is hydrogen or alkyl.
 11. The compound according to claim 1wherein R₂ is a mono-substituted phenyl wherein the substituents areindependently selected from the group consisting of hydrogen, halo,S(O)_(m) R₆, OR₉, or C₁₋₄ alkyl.
 12. The compound according to claim 1wherein R₁ is 4-pyridyl substituted in the 2-position with a C₁₋₄ alkyl.13. The compound according to claim 1 wherein R₂ is a mono-substitutedphenyl wherein the substitutents are independently selected from thegroup consisting of hydrogen, halo, S(O)_(m) R₆, OR₉, or C₁₋₄ alkyl; ris 0, s is 1, Q is aryl, Y is hydrogen, alkyl, --(C(R₁₀)₂)_(n) OR₈,--(C(R₁₀)₂)_(n) S(O)_(m') R₁₁, --(C(R₁₀)₂)_(n) SR₈, --(C(R₁₀)₂)_(n)S(O)_(m') OR₈, --(C(R₁₀)₂)_(n) S(O)_(m') NR₈ R₉, --X_(a) --P(Z)--(X_(a)R₁₃)2, --(C(R₁₀)₂)_(n) NR₈ R₉, --(C(R₁₀)₂)_(n) CO₂ R₈, --(C(R₁₀)₂)_(n)OC(O)--R₈, --(C(R₁₀)₂)_(n) CONR₈ R₉, --(C(R₁₀)₂)_(n) NR₁₀ C(═NCN)--NR₈R₉, or --(C(R₁₀)₂)_(n) NR₁₀ S(O)_(m) R₁₁, R₄ is hydrogen or methyl, R₈is hydrogen, C₁₋₄ alkyl, or may optionally cyclize with R₉ to form a 5membered heterocyclic ring together with the nitrogen to which they areattached.
 14. The compound according to claim 1 whichis1--(4-pyridyl)-2-(4-fluorophenyl)-4-phenylimidazole;1--(4-pyridyl)-2-(4-fluorophenyl)-4-(4-hydroxyphenyl)imidazole;1--(4-pyridyl)-2-(4-fluorophenyl)-4-(4-thiomethylphenyl)imidazole;1--(4-pyridyl)-2-(4-fluorophenyl)-4-(4-methylsulfinylphenyl)imidazole;1--(4-pyridyl)-2-(4-fluorophenyl)-4-methylimidazole;1--(2-methylpyrid-4-yl)-2-(4-fluororphenyl)-4-(4-thiomethylphenyl)imidazole;or1--(2-methylpyrid-4-yl)-2-(4-fluorophenyl)-4-(4-methylsulfinylphenyl)imidazole.15. The compound according to claim 1 wherein R₂ is a phenyl mono- ordi-substituted independently by halogen.
 16. A pharmaceutical orveterinary composition comprising an effective amount of a compoundaccording to claim 1 and a pharmaceutically or veterinary acceptablecarrier or diluent.
 17. The pharmaceutical or veterinary compositioncomprising an effective mount of a compound according to claim 14 and apharmaceutically or veterinary acceptable carrier or diluent.
 18. Amethod of treating septic shock, endotoxic shock, gram negative sepsis,or toxic shock in a mammal in need thereof, which method comprisesadministering to said mammal an effective amount of a compound accordingto claim 1.